Many intracellular enzymes and receptors are targets for pharmaceutically useful drugs which modulate their activities by binding to their active sites. Examples appear in Table 1 below. To reach the target enzymes and receptors, modulator compounds must of course cross the cell membrane from plasma/extracellular fluid. In general, charge neutral modulators cross the cell membrane more easily than charged species. A dynamic equilibrium is then set up whereby the modulator equilibrates between plasma and cell interior. As a result of the equilibrium, the intracellular residence times and concentrations of many modulators of intracellular enzymes and receptors are often very low, especially in cases where the modulator is rapidly cleared from the plasma. The potencies of the modulators are therefore poor despite their high binding affinities for the target enzyme or receptor.
Our International Patent Application WO 2006/117567 discloses a method for increasing the intracellular concentration of a given modulator of an intracellular enzyme or receptor by conjugating thereto an α-amino acid ester motif which is hydrolysed by one or more of the intracellular carboxylesterases hCE-1, hCE-2 and hCE-3. This results in increased potency by prolonging the residency of the modulator inside the cell, and leads to improved pharmacokinetic and pharmacodynamic properties. More consistent exposure and reduced dosing frequencies can be achieved. A further benefit is obtained when the α-amino add ester motif is conjugated to the modulator such that the drug is targeted to the specific target cells responsible for its therapeutic action, reducing systemic exposure and hence side effects.
The α-amino add ester conjugates disclosed in International Patent Application WO 2006/117567 are all mono-substituted on the α-carbon. That publication does not suggest that α,α-disubstituted glycine ester conjugates can be hydrolysed by intracellular carboxylesterases. In fact, it appears that the ability of the intracellular carboxyl esterases, principally hCE-1, hCE-2 and hCE-3, to hydrolyse α,α-disubstituted glycine ester has not previously been investigated.